This invention provides a method for treating and preventing neurological disorders such as Alzheimer""s disease, and for promoting wound healing, comprising administering a compound characterized as being a matrix metalloproteinase inhibitor.
Amyloid plaque formation is found in a number of diseases, including Alzheimer""s disease, scrapie, bovine spongiform encephalophy, Gerstmann-Straussler Syndrome, and the like. The amyloid plaques comprise proteins bound together in a fibrillous matrix. Amyloidosis is the general name given to diseases and conditions characterized by the presence of amyloid protein. A number of different types of amyloid protein are known, and all types are considered pathological, since no normally occurring amyloids are known. Accordingly, the presence of amyloid protein in a host is an indication of abnormal formation of fibrils and plaques. Amyloidosis has been clinically observed in a number of disease states, including certain mental illnesses, neurological diseases, and collagenosis. Indeed, the brains of subjects diagnosed with Alzheimer""s disease have one thing in common, namely an abundance of amyloid in the form of plaques and tangles.
Alzheimer""s disease is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment, and emotional stability that gradually leads to mental deterioration and ultimately death. Only two clinically approved treatments are available, one being tacrine hydrochloride (Cognex(copyright), from the Parke-Davis Division of Warner-Lambert Company). Because Alzheimer""s disease and related degenerative brain disorders are a major medical issue for an aging population, the need for new treatments and methods for diagnosing the disorders are needed.
We have now discovered that compounds which inhibit the enzymes that mediate the breakdown of connective tissues are useful for treating neurological disorders and wound healing. Such enzymes are known as native matrix metalloproteinases, which are classes of naturally occurring enzymes found in most mammals. They are zinc proteases that hydrolyze collagens, proteoglycans, and glycoproteins. The classes include gelatinase A and B, stromelysin-1 and -2, fibroblast collagenase, neutrophil collagenase, matrilysin, metalloelastase, and interstitial collagenase. These enzymes are implicated with a number of diseases which result from breakdown of connective tissues, such as rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, and even tumor metastasis. To date, inhibitors of matrix metalloproteinases have not been utilized to treat or prevent neurological disorders such as Alzheimer""s disease and Parkinson""s disease, or to promote wound healing. An object of this invention is to provide a method for treating and preventing neurological disorders and promoting wound healing metalloproteinase inhibitor.
This invention provides a method of treating and preventing neurological disorders and promoting wound healing by administering an effective amount of a matrix metalloproteinase inhibitor.
The method can be practiced by administering any chemical compound that is effective in inhibiting the biological activity of a matrix metalloproteinase such as collagenase, stromelysin, gelatinase or elastase. Numerous compounds are known to be matrix metalloproteinase inhibitors, and any of such compounds can be utilized in the method of this invention.
In a preferred embodiment, the matrix metalloproteinase inhibitor to be utilized is a substituted bicyclic compound of the formula 
wherein:
A is phenyl or 
where
Y is CH or N;
R1 is a substituent such as alkyl, aryl, halo, amino, substituted and disubstituted amino, and alkoxy;
R2 is carboxyalkyl ketone or oxime, or a carboxyalkyl sulfonamide such as 
where R3 is alkyl, substituted alkyl, amino, substituted and disubstituted amino, and aryl.
A particularly preferred embodiment is a method of treating and preventing neurological disorders and wound healing by administering a biphenylsulfonamide such as 
In another embodiment, neurological disorders and wound healing are treated or prevented by administering a matrix metalloproteinase which is a substituted fused tricyclic compound of the formula 
where R1 and R2 are as defined above, T is O, S5 (O)0,1, or 2, Cxe2x95x90O, NR3, or 
and W, W1, Z, and Z1 are each the same or different and each is CR3,
where R3 is alkyl, halo, alkoxy, acyl, and aryl. A preferred method utilizes dibenzofurans of the above formula, for instance compounds such as 
where R2 is, for instance, 
All of the matrix metalloproteinase inhibitors to be utilized in the method of this invention are either known or are readily available by common synthetic processes.